Hepatic covalent adduct formation with zomepirac in the CD26-deficient mouse

doi:10.1046/j.1440-1746.2002.02662.x

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Wiley InterScience

Journal of Gastroenterology and Hepatology

Volume 17 Issue 1, Pages 66 - 71

Published Online: 15 Mar 2002

Published in partnership with the Journal of Gastroenterology and Hepatology Foundation

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Hepatic covalent adduct formation with zomepirac in the CD26-deficient mouse

MIN WANG*, MARK D GORRELL†, CATHERINE A ABBOTT†, RENE JAGGI*, DIDIER MARGUET‡ AND RONALD G DICKINSON*

*Department of Medicine, University of Queensland, Royal Brisbane Hospital, Brisbane, †A.W. Morrow Gastroenterology and Liver Center, Royal Prince Alfred Hospital, Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Sydney, Australia and ‡Centre d'Immunologie de Marseille Luminy, Institut National de la Sante et de la Recherche Medicale-Centre National de la Recherche Scientifique Case 906, Marseille, France

Correspondence: Prof. Ronald G Dickinson, Department of Medicine, Clinical Sciences Building, Royal Brisbane Hospital, QLD 4029, Australia. Email: r.dickinson@medicine.uq.edu.au

KEYWORDS

acyl glucuronide • CD26 • covalent adduct formation • dipeptidyl peptidase IV • zomepirac

ABSTRACT

Background and Aims:

Background and Aims:Zomepirac (ZP), a non-steroidal anti-inflammatory drug (NSAID), has been reported to cause immune-mediated liver injury. In vivo, ZP is metabolized to a chemically reactive acyl glucuronide conjugate (ZAG) which can undergo covalent adduct formation with proteins. Such acyl glucuronide-derived drug-protein adducts may be important in the development of immune and toxic responses caused by NSAID. We have shown using immunoabsorptions that the 110 kDa CD26 (dipeptidyl peptidase IV) is one of the hepatic target proteins for covalent modification by ZAG. In the present study, a CD26-deficient mouse strain was used to examine protein targets for covalent modification by ZP/metabolites in the liver.

Methods and Results:

Methods and Results:The CD26-deficient phenotype was confirmed by immunohistochemistry, flow cytometry analysis, RT-PCR, enzyme assay and immunoblotting. Moreover, by using monoclonal antibody immunoblots, CD26 was not detected in the livers of ZP-treated CD26-deficient mice. Immunoblots using a polyclonal antiserum to ZP on liver from ZP-treated mice showed three major sizes of protein bands, in the 70, 110 and 140 kDa regions. Most, but not all, of the anti-ZP immunoreactivity in the 110 kDa region was absent from ZP-treated CD26-deficient mice.

Conclusion:

Conclusion:These data definitively showed that CD26 was a component of ZP-modified proteins in vivo. In addition, the data suggested that at least one other protein of approximately 110 kDa was modified by covalent adduct formation with ZAG.

DIGITAL OBJECT IDENTIFIER (DOI)

10.1046/j.1440-1746.2002.02662.x About DOI